PB1812: CO-MUTATION PROFILE IN A REAL-LIFE COHORT OF ACUTE MYELOID LEUKEMIA (AML)
Authors: Giovanna Piras, Antonella Cucca, Maria Itria Monne, Antonella Uras, Francesco Longu, Anna Calvisi, Maria Antonia Isoni, Francesca Cambosu, Paola Maria Campus, Marco Murineddu, Luigi Benedetto Arru, Alessandro Bianchi, Alessandro Murgia, Melissa Vacca, Claudio Fozza, Angelo Domenico Palmas
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Next-generation sequencing (NGS) technology is nowadays clinically applicable and represents standard of care. The definition of the genetic lesions present in acute myeloid leukemia (AML) patients, leds to improved disease classification, risk stratification and guide towards a personalized treatment. The 2022 European LeukemiaNet (ELN) recommendations for genetic risk stratification of AML have been widely adopted among physicians, eventhough patient responses remain heterogeneous. Aims: to retrospectively analyze clinical significant co-mutational patterns in a real-life cohort of AML patients. Methods: A retrospective analysis of 136 newly diagnosed AML patients and treated in two Sardinia (Italy) hematological centers was performed. Median age was 65 years (18-89), female were 52 (38%) and 41% of pts were >70 yrs old. According to WHO 2022, the AML cohort was classified as follows: 50 AML with recurrent genetic abnormalities (AML-RGA), 37 AML with myelodisplasia-related changes (AML-MRC), 19 TP53-mutant AML, 30 AML not otherwise specified (AML-NOS). DNA samples were analyzed at diagnosis by targeted NGS on Ion Torrent platform using the DNA Oncomine Myeloid Research panel which explores 1256 hotspots in 33 key myeloid genes. Demographic and clinical data, cytogenetic and molecular characteristics at diagnosis, first-line treatment and clinical outcome data were available for all patients. Results: ELN2022 risk stratification system assigned 22 patients to the favorable, 50 to intermediate and 64 to the adverse risk groups with a mean overall survival (OS) of 75.8 +±17.1, 29.5+±4.7, 15.2+±2.3 months, respectively (p value = 0.0031), confirming a better stratification of the new system when compared to the ELN2017 (mean OS 56,5+±13,9; 28,7+±5,9 and 13+±2,5 months, p value=0,064). NGS detected 284 clinically relevant mutations in 93% AML patients with a limit of detection of 2%, while fusion genes were detected in 8% pts.Thirthy-one cases carried >≥3 altered genes. The most frequent abnormalities were FLT3ITD/TKD and NPM1 mutations which represented the 23% and 29%, respectively. Co-occurrence of NPM1mut and FLT3mut was had a frequency of 14%. IDH1/2 mutations were observed in 29/136 patients (21%) and were associated with NPM1mut and DNMT3Amut in 10 and 6 AMLs, respectively. RUNX1 gene was mutated in 17 patients (12,5%) and TP53 variants were observed with a frequency of 13%. Overall DNMT3A alterations accounted for the 22%, with about half affecting the R882 codon. Co-presence of DNMT3A either with TET2, ASXL1 or SRSF2 gene mutations (DTAS mut) was detected in 47/136 pts (34%) with higher frequency (76%) in patients older than 60 years. The DTAS mut profile was present in the 54% of ELN2022 adverse risk group. In the favorable and intermediate groups DNMT3A mutations co-occurred with different gene alterations without statistically significant impact in the OS. With respect to WHO classes, the AML-RGA group showed a prevalence of DNMT3Amut alone or in combination, while mutations in TET2, ASXL1 and SRSF2 were more represented in the AML-MRC group. Summary/Conclusion: Overall survival analysis showed a statistically significant difference when ELN 2022 risk groups were compared to ELN2017, as well as among WHO 2022 AML classes, confirming an improvement of the new classification and risk stratification systems. TP53 variants occurred in the absence of other gene mutations and were associated with a shorter OS, as expected. The triple mutation pattern of FLT3ITD-NPM1mut -DNMT3A mut was the most frequent combination both in young and older patients without impact on outcomes. DTAS mutations did not affect OS in our setting. Keywords: Hematological malignancy, AML, Acute myeloid leukemia